Role of 5-hT2C receptors in the hypophagic effect of m-CPP, ORG 37684 and CP-94,253 in the rat

Compounds that stimulate 5-HT2C and/or 5-HT1B receptors induce hypophagia, but the relative role of these receptors in the control of feeding behaviour remains to be unequivocally demonstrated. The objectives of the present study were: (a) comparison of the hypophagic effect of the mixed 5-HT2C/1B receptor agonist, m-CPP, with that of ORG 37684 and CP-94,253, a relatively selective 5-HT2C and 5-HT1B receptor agonist, respectively; (b) verification of the contribution of 5-HT2C receptors to the hypophagic effect of these compounds by antagonism experiments; and (c) to test whether cotreatment with ORG 37684 and CP-94,253 leads to a more pronounced reduction of food intake as compared with treatment with either compound alone. Food intake was measured in a free feeding experimental protocol employing female Wistar rats. m-CPP was more potent in suppressing food intake than ORG 37684 and CP-94,253 (ED50 values for the first hour of access: 0.45, 1.84 and 3.48 mg/kg ip, respectively). The 5-HT2C receptor antagonists, metergoline and SB 242.084, completely reversed the hypophagic effect of ORG 37684, but not that of CP-94,253 and m-CPP. The hypophagic effect of ORG 37684 was potentiated by a low (inactive) dose of CP-94,253 (ED50: 4.95 and 2.44 mg/kg ip after vehicle and CP-94,253 pretreatment, respectively) and vice versa (ED50 values: 4.02 and 0.62 mg/kg ip). It is concluded that the hypophagic effect of ORG 37684-but not that of m-CPP and CP-94,253--is exclusively mediated by activation of 5-HT2C receptors. The results further indicate that simultaneous activation of 5-HT2C and 5-HT1B receptors underlies the higher potency of m-CPP in reducing food intake, as compared with other, more selective, compounds.     

Role of 5-HT3 and 5-HT2C receptors located within the medial amygdala in the control of salt intake in sodium-depleted rats

In the present study, we investigated the role of 5-HT(3) and 5-HT(2C) receptors located within the medial amygdala (MeA) in the control of water and salt intake in sodium-depleted rats. Pharmacological activation of 5-HT(3) receptors located in the medial amygdala by the selective 5-HT(3) receptor agonist m-CPBG significantly reduced salt intake in sodium-depleted rats, an effect that is reverted by pretreatment with the selective 5-HT(3) receptor antagonist ondansetron. In addition, the injection of ondansetron alone into the medial amygdala had no effect on salt intake in sodium-depleted and in sodium-repleted rats. Pharmacological stimulation of 5-HT(2C) receptors located in the medial amygdala by the selective 5-HT(2C) receptor agonist m-CPP failed to modify salt intake in sodium-depleted rats, whereas the blockade of these receptors by the selective 5-HT(2C) receptor antagonist SDZ SER 082 significantly reduced salt intake in this same group of animals. These results lead to the conclusion that the pharmacological activation of 5-HT(3) receptors located within the MeA inhibits salt intake in sodium-depleted rats and that, in this same brain region, the functional integrity of 5-HT(2C) receptors is required to achieve the full expression of sodium appetite in sodium-depleted rats.     

5-HT2C receptors inhibit and 5-HT1A receptors activate the generation of spike-wave discharges in a genetic rat model of absence epilepsy

The present study was conducted to investigate the role of 5-HT(2C) and 5-HT(1A) receptors in the generation of spike-wave discharges (SWD) in the genetic absence epilepsy model Wistar Albino Glaxo rats from Rijswijk, Netherlands (WAG/Rij rats). We have determined the effects of the 5-HT(2C) receptor preferring agonist m-chlorophenyl-piperazine (m-CPP), the selective 5-HT(2C) receptor antagonist SB-242084, the selective 5-HT(1A) receptor antagonist WAY-100635, two selective serotonin re-uptake inhibitors (SSRI, fluoxetine and citalopram) and their combinations in this model. The 5-HT(2C) agonist m-CPP caused marked, dose-dependent decreases in the cumulative duration and number of SWD administered either intraperitoneally (0.9 and 2.5 mg/kg) or intracerebroventricularly (0.05 and 0.1 mg/kg). Treatment with SB-242084 (0.2 mg/kg, ip) alone failed to cause any significant change in SWD compared to vehicle. Pretreatment with SB-242084 (0.2 mg/kg, ip) eliminated the effects of m-CPP on SWD. Fluoxetine (5.0 mg/kg, ip) alone caused moderate increase in SWD. After pretreatment with SB-242084, the effect of fluoxetine was significantly enhanced. The combination of SB-242084 and citalopram (2.5 mg/kg, ip) caused a similar effect, namely an increase in SWD. In contrast, pretreatment with WAY-100635 significantly attenuated the effect of fluoxetine. In conclusion, these results indicate that the increase in endogenous 5-HT produces a dual effect on SWD; the inhibition of epileptiform activity is mediated by 5-HT(2C), the activation by 5-HT(1A) receptors.     

m-CPP-induced self-grooming is mediated by 5-HT2C receptors

m-Chlorophenylpiperazine (m-CPP), a potent 5-HT receptor agonist, is known to induce self-grooming in rats and exacerbate symptoms in patients with obsessive-compulsive disorder (OCD). To characterise the possible role, 5-HT(2B) and 5-HT(2C) receptors play in m-CPP-induced self-grooming, subtype-selective receptor antagonists were used. m-CPP significantly increased the amount of self-grooming in male Sprague-Dawley rats. This effect followed a bell-shaped dose-response curve with a peak at 0.6 mg/kg, i.p. Pretreatment with SB-242084, a subtype-selective 5-HT(2C) receptor antagonist (0.1-0.5 mg/kg, i.p.), reversed m-CPP-induced self-grooming. In contrast, pretreatment with the subtype-selective 5-HT(2B) receptor antagonist SB-215505 (1 mg/kg, i.p) did not block the effect of m-CPP. Two days after depletion of brain 5-HT by p-chlorophenylalanine (p-CPA, 2 x 50, 2 x 100 mg/kg, i.p.) m-CPP-induced responses were significantly enhanced compared to controls. Our studies provide evidence that direct activation of 5-HT(2C) receptors mediate m-CPP-induced self-grooming and the depletion of brain 5-HT sensitizes these receptors.     

Differential effects of 5-HT1 and 5-HT2 receptor agonists on hindlimb movements in paraplegic mice

The effects induced by serotonergic (5-HT) agonists of the 5-HT1 and 5-HT2 subclasses were examined on hindlimb movement generation in adult mice completely spinal cord transected at the low thoracic level. One week postspinalization, intraperitoneal injection (0.5-10 mg/kg) of meta-chlorophenylpiperazine (m-CPP; 5-HT(2B/2C) agonist) or trifluoromethylpiperazine (TFMPP; 5-HT(1B) agonist) failed to induce locomotor-like movements. However, dose-dependent nonlocomotor movements were induced in air-stepping condition or on a motor-driven treadmill. In contrast, hindlimb locomotor-like movements were found after the injection of quipazine (5-HT(2A/2C) agonist; 1-2 mg/kg). Combined with L-DOPA (50 mg/kg, i.p.), low doses of quipazine but not of m-CPP and TFMPP produced locomotor-like and nonlocomotor movements in air-stepping condition or on the treadmill. Subsequent administration of m-CPP or TFMPP significantly reduced and often completely abolished the hindlimb movements induced by quipazine and L-DOPA. Altogether, these results demonstrate that 5-HT(2A/2C) receptor agonists promote locomotion while 5-HT(1B) and 5-HT(2B/2C) receptor agonists interfere with locomotor genesis in the hindlimbs of complete paraplegic mice. These results suggest that only subsets of spinal 5-HT receptors are specific to locomotor rhythmogenesis and should be activated to successfully induce stepping movements after spinal cord injury.     

Serotonin agonists increase transferrin levels via activation of 5-HT1C receptors in choroid plexus epithelium.

Choroid plexus epithelial cells are enriched in mRNA for proteins such as the iron carrier transferrin, which acts as a trophic factor in the brain. Choroid plexus epithelial cells also have a high density of 5-HT1C receptors linked to activation of the phosphoinositide (PI) hydrolysis second messenger system. The present studies show that the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potently increases PI hydrolysis and the levels of transferrin in primary cultures of rat choroid plexus epithelial cells. These effects are blocked by the 5-HT1C/5-HT2 receptor antagonists mesulergine and mianserin, but not by the 5-HT2 receptor-selective antagonist spiperone. Similarly, mesulergine and mianserin, but not spiperone, block the increases in transferrin levels and PI hydrolysis elicited by 5-carboxamidotryptamine (5-CT), a 5-HT1 receptor-selective agonist, and by serotonin. We conclude, therefore, that 5-HT1C receptor activation in the choroid plexus leads to an increase in the production of transferrin. By promoting transferrin synthesis in the choroid plexus, 5-HT may indirectly influence brain development and differentiation.     

gamma-Aminobutyric acid-serotonin interactions in healthy men: implications for network models of psychosis and dissociation.

BACKGROUND: This study tested the hypothesis that deficits in gamma-aminobutyric acid type A (GABA(A)) receptor function might create a vulnerability to the psychotogenic and perceptual altering effects of serotonergic (5-HT(2A/2C)) receptor stimulation. The interactive effects of iomazenil, an antagonist and partial inverse agonist of the benzodiazepine site of the GABA(A) receptor complex, and m-chlorophenylpiperazine (m-CPP), a partial agonist of 5-HT(2A/2C) receptors, were studied in 23 healthy male subjects. METHODS: Subjects underwent 4 days of testing, during which they received intravenous infusions of iomazenil/placebo followed by m-CPP/placebo in a double-blind, randomized crossover design. Behavioral, cognitive, and hormonal data were collected before drug infusions and periodically for 200 min after. RESULTS: Iomazenil and m-CPP interacted in a synergistic manner to produce mild psychotic symptoms and perceptual disturbances without impairing cognition. Iomazenil and m-CPP increased anxiety in an additive fashion. Iomazenil and m-CPP interacted in a synergistic manner to increase serum cortisol. CONCLUSIONS: Gamma-aminobutyric acid-ergic deficits might increase the vulnerability to the psychotomimetic and perceptual altering effects of serotonergic agents. These data suggest that interactions between GABA(A) and 5-HT systems might contribute to the pathophysiology of psychosis and dissociative-like perceptual states.     

Involvement of 5-HT1B receptors in the anticonflict effect of m-CPP in rats

Summary The anticonflict activity of m-CPP, a non-selective agonist of 5-HT receptors, was studied in the drinking conflict test in rats. m-CPP administered in doses of 0.125–0. 5 mg/kg increased the number of punished licks, the maximum effect having been observed after a dose of 0.25 mg/kg. The anticonflict effect of m-CPP (0.25 mg/kg) was antagonized by the non-selective 5-HT antagonist metergoline (1–4 mg/kg) and by the -adrenoceptor blocker SDZ 21009 (2 and 4 mg/kg) with affinity for 5-HT_1A and 5-HT_1B receptors. On the other hand, the 5-HT_1A receptor antagonist NAN-190 (0.5 and 1 mg/kg), the 5-HT₂ receptor antagonist ritanserin (0.25 and 0.5 mg/kg), and the -blockers betaxolol (8 mg/kg) and ICI 118,551 (8 mg/kg) with no affinity for 5-HT receptors did not affect the effect of m-CPP. The effect of m-CPP was not modified, either, in animals with the 5-HT lesion produced by p-chloroamphetamine.These results suggest that the anticonflict effect of m-CPP described above results from stimulation of 5-HT_1B receptors — most probably these which are located postsynaptically.     

Involvement of 5-HT receptors in the regulation of food intake in Siberian hamsters

The Siberian hamster provides a physiological model for understanding the hypothalamic control of energy metabolism as it undergoes annual photoperiod-regulated cycles of body weight (i.e. fattening in summer, and catabolism of fat stores in winter). As a first step to investigate whether enhanced serotonergic (5-HT) tone might underlie the catabolic processes in short days, we investigated whether serotonergic stimulation can produce catabolic actions in fat hamsters housed in long days. Acute treatment with the serotonin reuptake inhibitor (+/-) fenfluramine (8 mg/kg, i.p.) produced a prolonged, dose-dependent reduction in food intake in both photoperiods. Behavioural observations and radiotelemetry analyses revealed that this anorectic effect of fenfluramine was associated with short-term increases in locomotor activity and in core body temperature. In a subsequent series of studies, hamsters were pretreated with the 5-HT2C receptor antagonist SB242084 (4 mg/kg, i.p.). This 5-HT2C receptor antagonist completely blocked the anorectic actions of fenfluramine, but did not decrease the hyperthermia or hyperlocomotion induced by fenfluramine; thus, the anorectic actions of fenfluramine probably reflect actions via the 5-HT2C receptor. Consistent with these observations, treatment of hamsters with the 5-HT2C receptor agonist VER 3323 (10 mg/kg, i.p.) or the 5-HT1B/2C receptor agonist mCPP (3 mg/kg, i.p.) reduced food intake. The response to manipulation of serotonergic pathways was not affected by the ambient photoperiod in any of these studies. We conclude that the anorectic actions of fenfluramine are not an indirect consequence of serotonergic actions on arousal pathways, and that its actions on feeding in the Siberian hamster are most likely to be mediated by the 5-HT2C receptor.     

Central 5-HT2B/2C and 5-HT3 receptor stimulation decreases salt intake in sodium-depleted rats

In the present study, we investigated the participation of central 5-HT(2B/2C) and 5-HT(3) receptors in the salt intake induced by sodium depletion in Wistar male rats. Sodium depletion was produced by the administration of furosemide associated with a low salt diet. Third ventricle injections of mCPP, a 5-HT(2B/2C) agonist, at doses of 80, 160 and 240 nmol, promoted a dose-dependent reduction in salt intake in sodium-depleted rats. The inhibitory effect produced by central administration of mCPP was abolished by the central pretreatment with SDZ SER 082, a 5-HT(2B/2C) antagonist. Similar results were obtained with third ventricle injections of m-CPBG (80, 160 and 240 nmol), a selective 5-HT(3) agonist that also induced a dose-related decrease in salt intake in sodium-depleted rats. The central pretreatment with LY-278,584, a selective 5-HT(3) receptor antagonist, was able to impair the salt intake inhibition elicited by third ventricle injections of m-CPBG. Central administration of each one of the antagonists alone or a combination of both antagonists together did not significantly change salt intake after sodium depletion. On the other hand, the central administration of both mCPP and m-CPBG, in the highest dose used to test their effect on salt intake (240 nmol), was unable to modify blood pressure in sodium-depleted rats. It is concluded that: (1) pharmacological activation of central 5-HT(2B/2C) and 5-HT(3) receptors diminishes salt intake during sodium depletion, (2) an inhibitory endogenous drive exerted by central 5-HT(2B/2C) and 5-HT(3) receptors does not seem to exist and (3) the reduction in salt intake generated by the pharmacological activation of these central receptors is not produced by an acute hypertensive response.     

Could the 5-HT1B receptor inverse agonism affect learning consolidation?

Diverse evidence indicates that, the 5-HT system might play a role in learning and memory, since it occurs in brain areas mediating such processes and 5-HT drugs modulate them. Hence in this work, in order to explore further 5-HT involvement on learning and memory 5-HT1B receptors' role is investigated. Evidence indicates that SB-224289 (a 5-HT1B receptor inverse agonist) post-training injection facilitated learning consolidation in an associative autoshaping learning task, this effect was partially reversed by GR 127935 (a 5-HT1B/1D receptor antagonist), but unaffected by MDL 100907 (a 5-HT2A receptor antagonist) or ketanserin (a 5-HT1D/2A/7 receptor antagonist) at low doses. Moreover, SB-224289 antagonized the learning deficit produced by TFMPP (a 5-HT1A/1B/1D/2A/2C receptor agonist), GR 46611 (a 5-HT1A/1B/1D receptor agonist), mCPP (a 5-HT2A/2C/3/7 receptor agonist/antagonist) or GR 127935 (at low dose). SB-224289 did not alter the 8-OH-DPAT (a 5-HT1A/7 receptor agonist) learning facilitatory effect. SB-224289 eliminated the deficit learning produced by the anticholinergic muscarinic scopolamine or the glutamatergic antagonist dizocilpine. Administration of both, GR 127935 (5mg/kg) plus ketanserin (0.01 mg/kg) did not modify learning consolidation; nevertheless, when ketanserin dose was increased (0.1-1.0mg/kg) and SB-224289 dose was maintained constant, a learning facilitation effect was observed. Notably, SB-224289 at 1.0mg/kg potentiated a subeffective dose of the 5-HT1B/1D receptor agonist/antagonist mixed GR 127935, which facilitated learning consolidation and this effect was abolished by ketanserin at a higher dose. Collectively, the data confirm and extend the earlier findings with GR 127935 and the effects of non-selective 5-HT(1B) receptor agonists. Clearly 5-HT1B agonists induced a learning deficit which can be reversed with SB-224289. Perhaps more importantly, SB-224289 enhances learning consolidation when given alone and can reverse the deficits induced by both cholinergic and glutamatergic antagonist. Hence, 5-HT1B receptor inverse agonists or antagonists could represent drugs for the treatment of learning and memory dysfunctions.     

Beta-endorphin responses to different serotonin agonists: involvement of corticotropin-releasing hormone, vasopressin and direct pituitary action

Activation of serotonergic neurotransmission has been shown to increase plasma beta-endorphin-like immunoreactivity (beta-End-LI). To study the mechanism(s) of this action, we measured the effects of 3 potent serotonin (5-HT) agonists with different structures and 5-HT receptor binding profiles in conscious unrestrained Sprague-Dawley rats in vivo and in dispersed anterior pituicytes in vitro. The 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), the 5-HT1C agonist, m-chlorophenylpiperazine (m-CPP), and the 5-HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), all markedly increased beta-End-LI in plasma in vivo. All 3 responses were blocked by dexamethasone pretreatment. Pituitary stalk transection (PST), as well as pretreatment with rabbit serum hyperimmune against rat corticotropin-releasing hormone (CRH, TS-6) completely abolished beta-End-LI response to 8-OH-DPAT and attenuated the responses by about 60% to DOI. Responses to m-CPP were markedly attenuated in PST rats, but pretreatment with TS-6 had no significant effect. To examine whether vasopressin (AVP) might be involved in the CRH neutralizing antibody-resistant beta-End-LI responses after m-CPP and DOI, we measured AVP concentrations after each agonist, m-CPP, but not DOI or 8-OH-DPAT, significantly elevated circulating AVP levels. As a proof of direct pituitary effect, DOI markedly stimulated beta-End-LI release from the anterior pituitary cell culture preparation in vitro. It was approximately as potent as CRH in the picomolar range, m-CPP was much less effective than DOI, while 8-OH-DPAT did not stimulate beta-End-LI release in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/2C, 5-HT3 and 5-HT4 receptors or 5-HT uptake inhibition: short- and long-term memory

In order to determine whether short- (STM) and long-term memory (LTM) function in serial or parallel manner, serotonin (5-hydroxtryptamine, 5-HT) receptor agonists were tested in autoshaping task. Results show that control-vehicle animals were modestly but significantly mastering the autoshaping task as illustrated by memory scores between STM and LTM. Thus, post-training administration of 8-OHDPAT (agonist for 5-HT(1A/7) receptors) only at 0.250 and 0.500 mg/kg impaired both STM and LTM. CGS12066 (agonist for 5-HT(1B)) produced biphasic affects, at 5.0 mg/kg impaired STM but at 1.0 and 10.0 mg/kg, respectively, improved or impaired LTM. DOI (agonist for 5-HT(2A/2C) receptors) dose-dependently impaired STM and, at 10.0 mg/kg only impaired LTM. Both, STM and LTM were impaired by either mCPP (mainly agonist for 5-HT(2C) receptors) or mesulergine (mainly antagonist for 5-HT(2C) receptors) lower dose. The 5-HT(3) agonist mCPBG at 1.0 impaired STM and its higher dose impaired both STM and LTM. RS67333 (partial agonist for 5-HT(4) receptors), at 5.0 and 10.0 mg/kg facilitated both STM and LTM. The higher dose of fluoxetine (a 5-HT uptake inhibitor) improved both STM and LTM. Using as head-pokes during CS as an indirect measure of food-intake showed that of 30 memory changes, 21 of these were unrelated to the former. While some STM or LTM impairments can be attributed to decrements in food-intake, but not memory changes (either increase or decreases) produced by 8-OHDPAT, CGS12066, RS67333 or fluoxetine. Except for animals treated with DOI, mCPBG or fluoxetine, other groups treated with 5-HT agonists 6 h following autoshaping training showed similar LTM and unmodified CS-head-pokes scores.     

5-HT1A and 5-HT7 receptors contribute to lurasidone-induced dopamine efflux

Lurasidone is a novel, atypical antipsychotic drug with serotonin [5-hydroxytryptamine (5-HT)]2A, 5-HT7, dopamine (DA) D2 antagonist, and 5-HT1A receptor partial agonist properties. The ability of lurasidone to reverse the effects of subchronic administration phencyclidine, to impair novel object recognition in rats, an animal model of cognitive impairment in schizophrenia, is dependent, in part, on its 5-HT1A agonist and 5-HT7 receptor antagonist properties. We tested whether 5-HT1A partial agonism or 5-HT7 antagonism, or both, contributed to the ability of lurasidone to enhance cortical and hippocampal DA efflux, which may be related to its ability to improve cognition. Here, we report that lurasidone, 0.25 and 0.5, but not 0.1 mg/kg, subcutaneously, significantly increased DA efflux in the prefrontal cortex and hippocampus in a dose-dependent manner. Lurasidone, 0.5 mg/kg, also produced a smaller increase in DA efflux in the nucleus accumbens. Pretreatment with the 5-HT1A receptor antagonist, WAY100635 (0.2 mg/kg, subcutaneously), partially blocked the lurasidone-induced cortical and hippocampal DA efflux. Further, subeffective doses of the 5-HT1A receptor agonist, tandospirone (0.2 mg/kg), or the 5-HT7 antagonist, SB269970 (0.3 mg/kg), potentiated the ability of a subeffective dose of lurasidone (0.1 mg/kg) to increase DA efflux in the prefrontal cortex. These findings suggest that the effects of lurasidone on the prefrontal cortex and hippocampus, DA efflux are dependent, at least partially, on its 5-HT1A agonist and 5-HT7 antagonist properties and may contribute to its efficacy to reverse the effects of subchronic phencyclidine treatment and improve schizophrenia.     

Medial parabrachial nucleus neurons modulate d-fenfluramine-induced anorexia through 5HT2C receptors

We previously reported that lesions of the medial parabrachial nucleus (PBN) enhanced d-fenfluramine (DFEN)-induced anorexia; a finding that suggests these lesions may potentiate the release of serotonin (5HT) or increase the postsynaptic action of 5HT. In the present study, we used SB 206553 (a 5HT2B/2C receptor antagonist) or m-CPP (a 5HT2C/1B receptor agonist) in a standard behavioral procedure (deprivation-induced feeding) to further explore the role of the medial PBN in drug-induced anorexia. In Experiment 1, DFEN (0 or 1.0 mg/kg) was given alone or in combination with SB 206553 (2.0 or 5.0 mg/kg). In Experiment 2, we investigated the food-suppressive effects of m-CPP (0.5, 1.0 or 2.0 mg/kg). The results of Experiment 1 show that SB 206553, while having no influence on the performance of control subjects, attenuated (2.0 mg/kg) or abolished (5 mg/kg) the potentiating effect of the lesions on DFEN-induced anorexia. In Experiment 2, m-CPP induced a suppression of food intake in nonlesioned animals that was significantly potentiated in rats with medial PBN lesions. These results are consistent with the hypothesis that medial PBN neurons mediate anorexia through 5HT2C receptors.     

Improvement of the isolation-induced social behavioural deficit involves activation of the 5-HT1B receptors

1. Mice were isolated for 7-9 days. An isolated mouse and a mouse reared in group showed a difference in their behaviour when observed together under an inverted beaker. The isolated mouse makes one half escape attempts in regard to the grouped mouse. This is considered as a social behavioural deficit. 2. 1- 3-(trifluoromethyl)phenyl piperazine (TFMPP), 1-(3-chlorophenyl)piperazine (m-CPP) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl) 1-H indole (RU-24969) activating preferentially the 5-HT1B receptors increased the number of escape attempts of the isolated mice up to the level of grouped mice. 3. Penbutolol, a beta-blocking drug acting also at 5-HT1 receptors, devoid of effect when given alone, antagonized significantly and dose-dependently the effects of TFMPP, m-CPP and RU-24969. 4. The interaction between TFMPP and five various serotonin antagonists was examined. Neither the 5-HT2 receptor antagonist ritanserine, the 5-HT3 receptor antagonist ICS 205-930, the 5-HT1C receptor antagonists mianserin and cyproheptadine antagonized the effect of TFMPP. The neuroleptic spiperone decreased by itself the number of escape attempts and opposed the TFMPP effect. 5. Taken together, these results suggest that the isolation-induced social behavioural deficit may be considered as a behavioural model responsive to 5-HT1B agonists.     

Allelic variants of the serotonin(2C) receptor and neuroendocrinological responses to the serotonin(2C) receptor agonist m-chlorophenylpiperazine in healthy male volunteers

The neurotransmitter serotonin (5-HT) possesses several receptors and their subtypes, some of which are polymorphic, such as the 5-HT(2C) receptor. The latter has been implicated in the control of neuroendocrine function, and has been discussed in the pathophysiology and pharmacotherapy of psychiatric disorders such as obsessive-compulsive disorder, panic disorder and bipolar affective disorder. To investigate whether the 5-HT(2C) receptor polymorphism contributes to the variation of neuroendocrinological responses elicited by activation of the hypothalamic-pituitary axis, we performed an m-chlorophenylpiperazine (m-CPP) challenge and monitored m-CPP and ACTH, cortisol and prolactin plasma levels in 16 healthy male volunteers carrying the common 5-HT(2C)-cys-23 receptor gene and 16 healthy male volunteers carrying the less frequent 5-HT(2C)-ser-23 receptor gene. The 5-HT(2C) polymorphism contributed little to the variation of the scores regarding hormonal responses of ACTH, cortisol and prolactin to the m-CPP challenge. The group carrying the rare 5-HT(2C)-ser-23 receptor gene showed a faster and stronger but not statistically significant ACTH response to the challenge. However, it is noteworthy that there is a 'medium' effect size of the ACTH response according to the conventions of Cohen, and thus comparable to other studies. Both groups show similar major scores in the Temperament and Character Inventory (TCI).     

SKF83959 suppresses excitatory synaptic transmission in rat hippocampus via a dopamine receptor-independent mechanism

Dopamine (DA) profoundly modulates excitatory synaptic transmission and synaptic plasticity in the brain. In the present study the effects of SKF83959, the selective agonist of phosphatidylinositol (PI)-linked D(1) -like receptor, on the excitatory synaptic transmission were investigated in rat hippocampus. SKF83959 (10-100 μM) reversibly suppressed the field excitatory postsynaptic potential (fEPSP) elicited by stimulating the Schaffer's collateral-commissural fibers in CA1 area of hippocampal slices. However, the inhibition was not blocked by the D(1) receptor antagonist SCH23390, the D(2) receptor antagonist raclopride, the 5-HT(2A/2C) receptor antagonist mesulergine, or the α(1) -adrenoceptor antagonist prazosin. In addition, SKF83959 inhibited the afferent volley and significantly reduced the paired-pulse facilitation ratios. In dissociated hippocampal CA1 pyramidal neurons, SKF83959 had no detectable effect on glutamate-induced currents but potently inhibited voltage-activated Na(+) current (IC50 value = 26.9 ± 1.0 μM), which was not blocked by SCH23390 or by intracellular dialysis of GDP-β-S. These results demonstrate that SKF83959 suppressed the excitatory synaptic transmission in hippocampal CA1 area, which was independent of D(1) -like receptor. The mechanism underlying the effect could be mainly inhibition of Na(+) channel in the afferent fibers. The suppression of excitatory synaptic transmission and the Na(+) channel by SKF83959 may contribute to its therapeutic benefits in Parkinson's disease.     

The effect of novel antipsychotics in rat oral dyskinesia

Rosengarten, Helen, Jack W. Schweitzer and Arnold J. Friedhoff: The Effect of Novel Antipsychotics in Rat Oral Dyskinesia. Prog. Neuro. Psychopharmacol. & Biol. Psychiat 1999, 23, pp. 1389–1404.

1. 1. The effect of the D1 agonist SKF38393 and the 5HT₂ C agonist m-CPP on repetitive jaw movements (RJM) was studied in rats. Acute administration of SKF38393 and/or m-CPP induced RJM in a dose dependent manner. In rats treated with both drugs, RJM responses were about equal to the sum of those obtained with each drug alone.

2. 2. The induction of RJM by SKF38393 was somewhat lower in rats pretreated with 5HT₂C receptor antagonist, mianserin, whereas mianserin severely reduced RJM induced by m-CPP alone.

3. 3. D1 antagonist SCH23390 inhibited SKF38393 induced RJM but had no effect on m-CPP induced chewing behavior.

4. 4. The present study confirms earlier evidence that D1 agonists used at optimal doses for the induction of RJM do not involve the serotonergic system in a significant way. It does, however, implicate the system in the emergence of drug induced oral behavior in rats.

5. 5. The effect of the atypical antipsychotics , clozapine, olanzapine and risperidone was studied on SKF38393 and m-CPP induced RJM. Pretreatment with the atypical antipsychotics clozapine and olanzapine inhibit SKF38393 and m-CPP induced RJM. Pretreatment with risperidone inhibits m- CPP induced oral behavior in rats while increases dose dependently SKF38393 induced RJM.

     

Identification of 5-hydroxytryptamine1D binding sites in human brain membranes

High-affinity, specific 3H-5-hydroxytryptamine (5-HT) binding was analyzed in membrane homogenates of human frontal cortex, caudate, and globus pallidus. 5-HT1A and 5-HT1C binding sites were pharmacologically blocked using 100 nM 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) and 100 nM mesulergine, respectively. The majority of 5-HT1 sites remained in each of the three brain regions under these conditions. The pattern of nucleotide interactions with these binding sites (GppNHp = GTP = GDP greater than GMP = adenine nucleotides) suggests a possible linkage to a G protein. RU 24969 competition studies confirmed the absence of 5-HT1B binding sites in human cortex, caudate, and globus pallidus. Drug interactions with putative 5-HT1D binding sites in bovine caudate membranes correlated significantly with their affinities for human membrane recognition sites labeled by 3H-5-HT in the presence of 100 nM 8-OH-DPAT + 100 nM mesulergine. We conclude that the majority of 3H-5-HT labeled recognition sites in human cortex, caudate, and globus pallidus represent 5-HT1D binding sites.